Daniels et al., U.S. Pat. No. 3,949,073, disclosed the preparation of soluble collagen by dissolving tissue in aqueous acid, followed by enzymatic digestion. The resulting atelopeptide collagen is soluble, and substantially less immunogenic than unmodified collagen. It may be injected into suitable locations of a subject with a fibril-formation promoter (described as a polymerization promoter in the patent) to form fibrous collagen implants in situ, for augmenting hard or soft tissue. This material is now commercially available from Collagen Corporation (Palo Alto, Calif.) under the trademark Zydcrm.RTM. Collagen Implant.
Miyata et al., U.S. Pat. No. 4,154,559, disclosed an ophthalmic drug delivery system comprising a chemically modified collagen thin membrane carrier.
Davis et al., U.S. Pat. No. 4,179,337, disclosed a physiologically active, water-soluble polypeptide composition comprising a physiologically active polypeptide coupled with a coupling agent to polyethylene glycol or polypropylene glycol.
Luck et al., U.S. Pat. No. 4,488,911, disclosed a method for preparing collagen in solution (CIS), wherein native collagen is extracted from animal tissue in dilute aqueous acid, followed by digestion with an enzyme such as pepsin, trypsin, or Pronase.RTM. (a trademark of American Hoechst Corporation, Somerville, N.J.). The enzymatic digestion removes the telopeptide portions of the collagen molecules, providing "atelopeptide" collagen in solution. The atelopeptide collagen in solution so produced is substantially nonimmunogenic, and is also substantially non-crosslinked due to loss of the primary crosslinking regions. The collagen in solution may then be precipitated by dialysis in a moderate shear environment to produce collagen fibers which resemble native collagen fibers. The precipitated, reconstituted fibers may additionally be crosslinked using a chemical agent (for example, aldehydes such as formaldehyde and glutaraldehyde), heat, or radiation. The resulting products are suitable for use in medical implants due to their biocomptibility and reduced immunogenicity.
Chu, U.S. Pat. No. 4,557,764, disclosed a "second nucleation" collagen precipitate which exhibits a desirable malleability and putty-like consistency. Collagen is provided in solution (e.g., at 2-4 mg/ml), and a "first nucleation product" is precipitated by rapid titration and centrifugation. The remaining supernatant (containing the bulk of the original collagen) is then decanted and allowed to stand overnight. The precipitated second nucleation product is collected by centrifugation.
Chu, U.S. Pat. Nos. 4,600,533; 4,655,980; 4,689,399; and 4,725,617, disclosed methods for preparing collagen membranes having high tensile strength by compressing and drying collagen gels.
Nguyen et al., U.S. Pat. No. 4,642,117, disclosed an injectable collagen material composed of reconstituted, mechanically sheared atelopeptide collagen fibers, which are prepared by passing reconstituted collagen fibers repeatedly through a rigid mesh screen, until a substantial reduction in fiber size and size heterogeneity is achieved. The mechanically sheared fibers may be subsequently crosslinked.
Ramshaw et al., U.S. Pat. No. 4,980,403, disclosed the precipitation of bovine collagen (types I, II, and III) from aqueous PEG solutions, where there is no binding between collagen and PEG.
Miyata et al., Japanese patent application 4-227265, published Aug. 17, 1992, discloses a composition comprising atelopeptide collagen linked to a polyepoxy compound. The composition is injected into the body to obtain sustained skin-lifting effects.
U.S. Pat. No. 5,162,430, issued Nov. 10, 1992 to Rhee et al., and commonly owned by the assignee of the present application, discloses collagen-synthetic polymer conjugates and methods of covalently binding collagen to synthetic hydrophilic polymers. This patent further disclosed binding biologically active agents to synthetic polymer molecules, then reacting with collagen to form a three-part collagen-synthetic polymer-active agent conjugate. Commonly owned, U.S. Pat. No. 5,292,802, issued Mar. 8, 1994, discloses methods for making tubes comprising collagen-synthetic polymer conjugates. Commonly owned, allowed U.S. application Ser. No. 07/922,541, filed Jul. 30, 1992, discloses various activated forms of polyethylene glycol and various linkages which can be used to produce collagen-synthetic polymer conjugates having a range of physical and chemical properties. Commonly owned, copending U.S. application Ser. No. 07/984,933, filed Dec. 2, 1992, discloses methods for coating implants with collagen-synthetic polymer conjugates.
Commonly owned, copending U.S. application Ser. No. 08/146,843, filed Nov. 3, 1993, discloses conjugates comprising various species of glycosaminoglycan covalently bound to synthetic hydrophilic polymers, which are optionally bound to collagen as well. Commonly owned, copending U.S. application Ser. No. 08/147,227, filed Nov. 3, 1993, discloses collagen-polymer conjugates comprising chemically modified collagens such as, for example, succinylated collagen or methylated collagen, covalently bound to synthetic hydrophilic polymers to produce optically clear materials for use in ophthalmic or other medical applications.
Commonly owned U.S. application Ser. No. 08/201,860, filed Feb. 17, 1994, discloses collagen-synthetic polymer conjugates prepared using collagens having controlled fiber size distributions, which can be obtained, for example, by manipulation of the pH of the collagen.
All publications cited above and herein are incorporated herein by reference to describe and disclose the subject matter for which it is cited.
We now disclose collagen-synthetic polymer conjugate compositions prepared using a multiple step reaction.